Interest in the medicinal chemistry of quinazoline derivatives was stimulated in the early 1950's with the elucidation of the structure of a quinazoline alkaloid, 3-[β-keto-gamma-(3-hydroxy-2-piperidyl)-propyl]-4-quinazolone, from an Asian plant known for its antimalarial properties. In a quest to find additional antimalarial agents, various substituted quinazolines have been synthesized. Of particular import was the synthesis of the derivative 2-methyl-3-o-tolyl-4-(3H)-quinazolinone. This compound, though ineffective against protozoa was found to be a potent hypnotic and is known by the name methaqualone.
The pharmacologic activity of quinazolinones and related compounds has been more thoroughly investigated since the introduction of methaqualone. Quinazolinones and derivatives thereof are now known to have a wide variety of biological properties including hypnotic, sedative, analgesic, anticonvulsant, antitussive and anti-inflammatory activities.
Quinazolinone derivatives for which specific biological uses have been described include 2-(substituted phenyl)-4-oxo-quinazolines with bronchodilator activity (U.S. Pat. No. 5,147,875). U.S. Pat. Nos. 3,723,432, 3,740,442, and 3,925,548 describe a class of 1-substituted-4-aryl-2(1H)quinazolinone derivatives useful as anti-inflammatory agents. European patent publication EP 0 056 637 B1 describes a class of 4(3H)-quinazolinone derivatives for the treatment of hypertension. European patent publication EP 0 884 319 A1 describes pharmaceutical compositions of quinazolin-4-one derivatives used to treat neurodegenerative, psychotropic, and drug and alcohol induced central and peripheral nervous system disorders.
Quinazolinones are among a growing number of therapeutic agents used to treat cell proliferative disorders, including cancer. For example, PCT WO 96/06616 describes a pharmaceutical composition containing a quinazolinone derivative to inhibit vascular smooth muscle cell proliferation. PCT WO 96/19224 uses this same quinazolinone derivative to inhibit mesengial cell proliferation. U.S. Pat. Nos. 4,981,856, 5,081,124 and 5,280,027 describe the use of quinazolinone derivatives to inhibit thymidylate synthase, the enzyme that catalyzes the methylation of deoxyuridine monophosphate to produce thymidine monophosphate, which is required for DNA synthesis. U.S. Pat. Nos. 5,747,498 and 5,773,476 describe quinazolinone derivatives used to treat cancers characterized by over-activity or inappropriate activity of tyrosine receptor kinases. U.S. Pat. No. 5,037,829 describes (1H-azol-1-ylmethyl) substituted quinazoline compositions to treat carcinomas that occur in epithelial cells. PCT WO 98/34613 describes a composition containing a quinazolinone derivative useful for attenuating neovascularization and for treating malignancies. U.S. Pat. No. 5,187,167 describes pharmaceutical compositions comprising quinazolin-4-one derivatives, which possess anti-tumor activity.
The synthesis of quinazolinones has been described, for example, by Ager et al., J. Med. Chem., 20:379–386 (1977). Quinazolinones have been obtained by acid-catalyzed condensation of N-acylanthranilic acids with aromatic primary amines. Other processes for preparing quinazolinones are described in U.S. Pat. Nos. 5,783,577, 5,922,866 and 5,187,167.
Syntheses of the class of quinazolinones presently of interest have been reported in WO 01/30768 (incorporated herein by reference) and are shown in Reaction Schemes A and B (below).

It has become particularly desirable to produce increased quantities of certain enantiomerically pure quinazolinones. It had previously been taught that such optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example: via formation of diastereoisomeric salts or complexes which can be separated, e.g., by crystallisation; via formation of diastereoisomeric derivatives which can be separated, e.g., by crystallisation, gas-liquid or liquid chromatography; via selective reaction of one enantiomer with an enantiomer-specific reagent, e.g., enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or via gas-liquid or liquid chromatography in a chiral environment, e.g., on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is described as potentially required to liberate the desired enantiomeric form. Alternatively, the asymmetric synthesis of specific enantiomers has been described using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation. An example of a prior synthesis from optically active starting materials is shown in Reaction Scheme B.

Notwithstanding such existing synthetic approaches, development of quinazolinones for new therapeutic indications has increased the need for producing these enantiomerically pure active agents. While effective for producing research quantities, the prior synthetic approaches are in many aspects too lengthy and uneconomical for production of larger scale batches of compound. Intermediate chemical resolutions require considerable time and result in relatively low yields. Moreover, certain reagents that are acceptable in small-scale syntheses (e.g., the use of bromine, sodium azide and triphenyl phosphine) are generally undesirable for large-scale production. Thus, there remains a need for improved quinzolinone syntheses, particularly for the larger scale production of enantiomerically pure quinazolinones